Biology subjects

Adler, F. R.

Publications and source records attributed to Adler, F. R..

9 recordsLinked to original sources

bioRxiv2026

Evolution of immune infiltration and immune triad formation across early melanoma progression

Tumor-infiltrating lymphocytes (TIL) in melanoma are a clinically important prognostic marker and are routinely used to inform patient care. However, when immune recognition of transformed melanocytes begins and how it evolves during early melanoma progression is not well understood. Using spatial transcriptomics and a unique cohort of patient-matched lesions representing multiple stages of early evolution, we investigate T cells, dendritic cells (DCs) and multi-cell immune "triads" during melanoma initiation. We find that T cell and DC density, triad density, and triad proximity to melanoma cells are elevated in regions of Stage I invasive melanoma as compared to Stage 0 in situ lesions and nevi. Further, we find that triad abundance correlates with both T cell and DC density, but is not predicted by clustering patterns of these cell types over larger spatial scales. We conclude that immune recognition of melanoma and engagement with the lesion significantly increases with progression from Stage 0 to Stage I disease. Further, using nevi that are depth-matched in the dermis to Stage I invasive lesions, we demonstrate this increased immune recognition is not a consequence of dermal invasion alone. This points to a paradigm where immune engagement of invasive melanoma reflects recognition of melanoma cell-intrinsic changes that emerge in Stage I disease.

cancer biology↗

bioRxiv2026

Clonal dynamics deviate from neutral drift in zebrafish spermatogenesis

Spermatogonial stem cells (SSCs) maintain male fertility, but how their clonal dynamics change with age remains poorly understood. Here, we use in vivo CRISPR barcoding in zebrafish to label SSCs and track their contributions to sperm production through monthly sampling across the fertile lifespan. We find that only a subset of embryonic germ cells contributes to adult sperm production and that the relative contributions of individual clones shift dramatically over time. To interpret these dynamics, we developed a mathematical model that quantifies clonal drift rates and formally tests neutral versus non-neutral hypotheses. Most SSC clones show significant evidence of drift, yet their dynamics are inconsistent with a neutral model where clones have equal fitness and their dynamics are driven solely by random chance. Instead, we observe heterogeneous clonal dynamics, including a positive relationship between clone size and drift rate. Together, these findings demonstrate that SSC clonal dynamics are non-neutral across the zebrafish reproductive lifespan with important implications for allele transmission.

developmental biology↗

bioRxiv2025

Influenza virus evolution and defective genome formation are shaped by host genotype and sex

Viral evolution during initial pandemic waves favors mutations that enhance replication and transmission over antigenic escape. Host genotype and sex strongly shape this early adaptation, yet their individual and combined effects remain unclear. We experimentally adapted influenza A virus to male and female BALB/c and C57BL/6 mice, generating 28 independent lineages, and employed a novel "rolling sphere" approach to identify mutational hotspots in three-dimensional protein structures. In BALB/c mice, adaptation favored nonsynonymous substitutions linked to increased virulence, including a hemagglutinin variant exclusively fixed in female lineages. It also revealed the first demonstration of sex-dependent selection shaping a viral protein interface. In female-adapted viruses, substitutions disrupting a key NS1 dimerization motif converged on a single residue, while in male-adapted viruses, they were dispersed across the same interface. Conversely, adaptation to C57BL/6 resulted in fewer substitutions but promoted defective viral genome formation, leading to reduced cytopathic effect and attenuated virulence. This provides the first in vivo evidence that host genotype alone can modulate defective viral genome formation. Our results offer critical insights into host-pathogen interactions and reveal that selective pressures imposed by specific genotype-sex combinations can increase virulence across host genotypes, enabling new epidemiological modeling and disease control strategies.

evolutionary biology↗

bioRxiv2022

Cancer cells communicate with macrophages to prevent T cell activation during development of cell cycle therapy resistance

Cancer cells evolve, acquire resistance to therapy and change their environment. One resistance mechanism involves altering communication with non-malignant cells in the tumor microenvironment (TME). By corrupting the signals for growth and survival, evolving cancer cells can engineer a pro-tumor TME. However, the specific interactions between malignant and non-malignant cells that predispose drug resistance and their changes during treatment remain widely unknown. Here we examine the composition, communication, and phenotypic diversity of tumor-associated cell populations in serial biopsies from early-stage ER+ breast cancers. These patients received either endocrine therapy (letrozole) alone or in combination with a CDK4/6 cell cycle inhibitor ribociclib, and were analyzed using single-cell RNA sequencing (scRNAseq). Our analyses reveal cancer cells from ribociclib resistant tumors stimulate macrophage differentiation towards an immune-suppressive phenotype through upregulation of a broad diversity of cytokines and growth factors. This shift in phenotype leads to reduced macrophage cell IL-15/-18 crosstalk with CD8+ T-cell via IL-2/15RA/18R receptors, resulting in diminished T-cell activation and recruitment. Thus, cancer communication promoting an immune-cold TME predispose tumors to develop CDK4/6 inhibitor resistance, and that the beneficial effects of cell cycle inhibitors through blocking cancer cell proliferation must be balanced against their known inhibitory effect on immune cell division and activation. An optimal treatment strategy will require coupling the prevention of cancer division with activation of an effective cytotoxic T-cell response.

cancer biology↗

bioRxiv2021

Facilitation drives estrogen receptor positive (ER+) breast cancer growth and survival under drug pressure

The interplay of positive and negative interactions between drug sensitive and resistant cells influences the effectiveness of treatment in heterogeneous cancer cell populations. In a study of isogenic estrogen receptor positive (ER+) breast cancer cell lineages sensitive and resistant to ribociclib-induced CDK4/6 inhibition in mono- and co-culture, we find that sensitive cells grow and compete more effectively in the absence of treatment. During treatment with ribociclib, sensitive cells survive and proliferate better when grown together with resistant cells than when grown in monoculture, termed facilitation in ecology. Both liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays and single cell RNA-sequencing (scRNAseq) indicate that resistant cell production of estradiol, a highly active estrogen metabolite, is the mechanism of facilitation. Higher estradiol production by resistant cells drives a shift in sensitive cell phenotype to a resistant cell state in coculture. Adding estradiol in monoculture provides sensitive cells with increased resistance to therapy, and cancels facilitation in coculture. Mathematical modeling quantifies the strength of competition and facilitation and predicts that blocking facilitation has the potential to control both resistant and sensitive cell populations and inhibit the emergence of a refractory population.

systems biology↗

bioRxiv2021

Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine inhibitors

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionary trajectories of early stage breast cancer tumors using serial tumor biopsies from a clinical trial of preoperative endocrine therapy (letrozole) alone or in combination with the cell cycle inhibitor ribociclib. Applying hierarchical regression and Gaussian process mathematical modelling, we classified each tumor by whether it shrinks or persists with therapy and determined cancer phenotypes related to evolution of resistance and cell cycle transcriptional rewiring. We found that all patients tumors undergo subclonal evolution during therapy, irrespective of the clinical response. However, tumors subjected to endocrine therapy alone showed reduced diversity over time, while those facing combination therapy exhibited increased diversity. Despite different subclonal diversity, single nuclei RNA sequencing uncovered common phenotypic changes in tumor cells that persist following treatment. In these tumors, cancer cells with accelerated loss of estrogen signaling have convergent up-regulation of the JNK pathway, while cells that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. These convergent phenotypes were associated with growing tumors resistant to combination therapy. Cell cycle reconstruction identified that these tumors can rebound during combination therapy treatment, indicating stronger selection and promotion of a proliferative state. These results indicate that combination therapy in early stage ER+ breast cancers with ER and CDK inhibition drives rapid evolution of resistance via a shift from estrogen signaling to alternative growth factor receptor mediated proliferation and JNK signaling activation, concordant with a bypass in the G1 checkpoint.

cancer biology↗

bioRxiv2020

What p53 sees: ATM and ATR activation through crosstalk between DNA damage response pathways

1Cells losing the ability to self-regulate in response to damage is a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process would be remarkable if it were based on the total amount of damage in the cell, but because damage detection pathways vary in the rate and intensity with which they promote pro-apoptotic factors, the cells real challenge is to reconcile dissimilar signals. Crosstalk between repair pathways, crosstalk between pro-apoptotic signaling kinases, and signals induced by damage byproducts complicate the process further. The cells response to{gamma} and UV radiation neatly illustrates this concept. While these forms of radiation produce lesions associated with two different pro-apoptotic signaling kinases, ATM and ATR, recent experiments show that ATM and ATR react to both forms of radiation. To simulate the pro-apoptotic signal induced by{gamma} and UV radiation, we construct a mathematical model that includes three modes of crosstalk between ATM and ATR signaling pathways: positive feedback between ATM/ATR and repair proteins, ATM and ATR mutual upregulation, and changes in lesion topology induced by replication stress or repair. We calibrate the model to agree with 21 experimental claims about ATM and ATR crosstalk. We alter the model by adding or removing specific processes, then examine the effects of each process on ATM/ATR crosstalk by recording which claims the altered model violates. Not only is this the first mathematical model of ATM/ATR crosstalk, its implications provide a strong argument for treating pro-apoptotic signaling as a holistic effort rather than attributing it to a single dominant kinase.

systems biology↗

bioRxiv2020

Rolling Signal-based Ripley's K: A new algorithm to identify spatial patterns in histological specimens

The spatial distribution of cells within a tissue underlies organ function. However, these spatial distributions are often difficult to identify, making it challenging to evaluate how cells establish these patterns during development or how diseases may disrupt these patterns and impair function. To address this, we developed an image analysis tool based on a novel algorithm that identifies spatial patterns within tissues. This analytical tool was used to study the bone marrow, a specialized microenvironment in which spatial patterning of regulatory cells may influence the differentiation and survival of hematopoietic stem cells. Using this algorithm, we discovered clusters of regulatory cells within the bone marrow that suggest an organization of micro-niches, which may form the basis of the hematopoietic stem cell microenvironment. This work provides a new tool for the detection and analysis of tissue morphology that enables identification of spatial patterns within tissues that can lead to a deeper understanding of tissue function, provide clues for early onset of disease, and be used as a tool for studying the impact of pharmaceutics on tissue development and regeneration. In BriefThis work introduces a new statistic to analyze the patterning of cells and physiological features in histological images. This statistic was used on a published set of immunofluorescent images of murine bone to identify novel spatial structures within the bone marrow that may provide new inisghts to the organization of the hematopoietic stem cell microenvironment. HighlightsO_LIRSRK, a statistical tool for analyzing the spatial distribution of features in histological images, is introduced. C_LIO_LIRSRK incorporates the quantification of signal distribution to identify unique spatial patterns. C_LIO_LISpatial patterns in hematopoietic stem cell microenvironments are identified. C_LI Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

systems biology↗

bioRxiv2020

Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell interactions in patients during immunotherapy

The extent that immune cell phenotypes in the peripheral blood reflect within-tumor immune activity prior to and early in cancer therapy is unclear. To address this question, we studied the population dynamics of tumor and immune cells, and immune phenotypic changes, using clinical tumor and immune cell measurements and single cell genomic analyses. These samples were serially obtained from a cohort of advanced gastrointestinal cancer patients enrolled on a trial with chemotherapy and immunotherapy. Using an ecological population model, fitted to clinical tumor burden and immune cell abundance data from each patient, we find evidence of a strong tumor-circulating immune cell interaction in responder patients, but not those patients that progress on treatment. Upon initiation of therapy, immune cell abundance increased rapidly in responsive patients, and once the peak level is reached, tumor burden decreases, similar to models of predator-prey interactions; these dynamic patterns were absent in non-responder patients. To interrogate phenotype dynamics of circulating immune cells, we performed single cell RNA sequencing at serial time points during treatment. These data show that peripheral immune cell phenotypes were linked to the increased strength of patients tumor-immune cell interaction, including increased cytotoxic differentiation and strong activation of interferon signaling in peripheral T-cells in responder patients. Joint modeling of clinical and genomic data highlights the interactions between tumor and immune cell populations and reveals how variation in patient responsiveness can be explained by differences in peripheral immune cell signaling and differentiation soon after the initiation of immunotherapy. One sentence summaryPeripheral immune cell differentiation and signaling, upon initiation of immunotherapy, reflects tumor attacking ability and patient response. Significance statementThe evolution of peripheral immune cell abundance and signaling over time, as well as how these immune cells interact with the tumor, may impact a cancer patients response to therapy. By developing an ecological population model, we provide evidence of a dynamic predator-prey like relationship between circulating immune cell abundance and tumor size in patients that respond to immunotherapy. This relationship is not found either in patients that are non-responsive to immunotherapy or during chemotherapy. Single cell RNA-sequencing (scRNAseq) of serial peripheral blood samples from patients show that the strength of tumor-immune cell interactions is reflected in T-cells interferon activation and differentiation early in treatment. Thus, circulating immune cell dynamics reflect a tumors response to immunotherapy.

cancer biology↗