Biology subjects

Rock, A.

Publications and source records attributed to Rock, A..

7 recordsLinked to original sources

bioRxiv2026

The Impact of Smoking Status on the Genomic Landscape of Lung Squamous Cell Carcinoma

PurposeComprehensive genomic profiling (CGP) has changed the treatment paradigm for non-small cell lung cancer (NSCLC) with the advent of molecularly targeted therapies for actionable genomic alterations (AGA). Despite this, the use of CGP is suboptimal, particularly in squamous cell lung cancer (sqNSCLC), which is more closely associated with smoking exposure and a lack of AGAs. We hypothesized that the prevalence of AGAs is inversely correlated with the chronicity and extent of smoking exposure in patients with sqNSCLC. Experimental DesignWe retrospectively evaluated all patients with liquid biopsy testing via Guardant 360CDX or Guardant360 in the context of any sqNSCLC diagnosis at the City of Hope Comprehensive Cancer Center between 10/2020 and 7/2023. The data was obtained on 2/23/24. Social and clinical histories were evaluated to assess the frequency of AGAs in patients with no or remote smoking history. ResultsOf the 56 patients in the initial evaluation, 24% (n=13) were non-smokers or remote smokers (greater than 20 years from cessation). Of these 13 patients, eight (61.5%) harbored AGA. Of these 8 patients, alterations observed included EGFR exon 19 deletion (50%, n=4), MET exon 14 skipping mutation (25%, n=2), EGFR G719S (13%, n=1), EGFR E114K (13%, n=1). Of those patients harboring AGAs that received NCCN-concordant matched targeted therapy, the objective response rate (ORR) with targeted agents was 50% and the clinical benefit rate (CBR) was 83.3%. ConclusionsThese data support the use of CGP in sqNSCLC particularly in patients with remote or no smoking exposure. Statement of translational relevanceThese data demonstrate high frequency of actionable genomic alterations (AGAs) in patients diagnosed with squamous cell lung cancer (sqNSCLC) with remote or no smoking history. Specifically, enrichment of EGFR and MET gene alterations were observed. These findings support the use of comprehensive molecular profiling in sqNSCLC. Furthermore, treatment outcomes demonstrate frequent objective responses and high clinical benefit rate supporting the use of targeted therapies in sqNSCLC harboring AGAs. This analysis provided rationale for further research of larger datasets investigating therapeutic approaches in sqNSCLC, which may have significant implications for consensus guideline recommendations and routine clinical practice.

cancer biology↗

bioRxiv2026

CA19-9 induces microenvironment remodeling in pancreatic ductal adenocarcinoma

Durable therapeutic efficacy remains a major barrier to improving outcomes for patients with pancreatic ductal adenocarcinoma (PDAC). An immunosuppressive tumor microenvironment (TME) is a hallmark of PDAC and has been demonstrated to be a dominant driver of therapeutic resistance. The aberrant glycan CA19-9 is prevalent in PDAC and drives tumor progression, but the paracrine mechanisms by which it contributes to TME remodeling are unknown. To address this, we mapped TME changes and performed functional analyses using a genetically engineered mouse model (GEMM) harboring KrasG12D mutation and inducible CA19-9 expression. Elevation of CA19-9 led to expansion of antigen-presenting cancer associated fibroblasts (apCAFs) and regulatory T cells (Tregs), which can drive immunosuppression. Antibody blockade of CA19 -9 resulted in significant restoration of normal histology and decreased apCAF and Treg populations. We dissected the paracrine signaling mechanisms that drive this TME remodeling in vitro using mouse and human organoid mono- and co-culture models as well as in vivo using GEMMs and syngeneic orthotopic transplantation models. CA19-9 induced IL1a and TGFb expression, reprogramming pancreatic mesothelial cells into apCAFs in vitro, which in turn directly ligated naive Cd4+ T cells resulting in Treg differentiation in co-cultures. Antibody blockade of IL1a and TGFb in mice led to reduced apCAF and Treg differentiation. We previously reported that CA19-9 modification of the secreted Fbln3 protein increased Egfr engagement and now find that the induction of IL1a and TGFb expression by CA19-9 is dependent on Fbln3 hyperactivation of EGFR signaling. Genetic depletion of Fbln3 led to reduced tumor progression and increased Cd8+ T cell infiltration in mice. Together these findings identify a previously unknown signaling axis driving immunosuppressive phenotypes in PDAC, uncovering multiple potential nodes to relieve the immunosuppressive pressures within the PDAC TME.

cancer biology↗

bioRxiv2026

A cell-nonautonomous heme acquisition pathway enables erythroid hemoglobinization under stress

Heme, an iron-containing cofactor, is synthesized in mitochondria by an eight-enzyme pathway. Although cells were thought to manage heme autonomously, over 1,000 proteins contribute to its production, transport, and regulation. During terminal erythroid differentiation, mitochondria are discarded yet hemoglobin production continues, implying a cell-nonautonomous heme supply. We show that, under stress, erythroblasts import heme through the permease Heme Responsive Gene 1 (HRG1), which localizes to the plasma membrane and accumulates during stress erythropoiesis, the emergency program that expands red cell output. HRG1 loss impaired heme uptake, inhibited terminal erythroid differentiation, and caused anemia. In {beta}-thalassemic mice, partial HRG1 loss reduces ineffective erythropoiesis, underscoring the importance of balanced heme import. These findings reveal intercellular heme sharing and identify HRG1 as a potential therapeutic target in hemoglobinopathies.

cell biology↗

bioRxiv2026

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation to an exhausted state. In healthy tissues, tissue-resident memory T cells (TRM) maintain protection for years, and patient tumors that contain TIL with TRM features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing TRM and progenitor-exhausted TIL from terminally-exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins in spite of functional proteasome activity. Enforced expression of these ligases by TIL preserved stem-like TCF1+ populations and improved anti-tumor function, whereas their knockout impaired TIL and altered T cell differentiation in acute infection. Sustained ligase expression rescued accumulation of unfolded proteins in TIL and improved immunotherapy outcome in preclinical models, highlighting the critical role of proteostasis in TIL function and identifying new avenues for advancing cancer immunotherapy.

immunology↗

bioRxiv2025

Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer

Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need to understand mechanisms of resistance. We used a novel approach to uncover metabolic adaptations that bypass autophagy inhibition. Utilizing PDA cells with acquired resistance to different autophagy inhibitors, we found that severe autophagy depletion induces metabolic rewiring to sustain TCA intermediates and nucleotides for biosynthesis. Long-term autophagy inhibition results in altered pyruvate metabolism likely regulated by lower pyrimidine pools. Cells adapting to loss of autophagy preferentially salvage pyrimidines to replenish these pools instead of synthesizing them de novo. Exploiting this metabolic vulnerability, we found that acquired resistance to autophagy inhibition promotes increased salvage and therefore sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil leading to combinatory effects with autophagy inhibitors and pyrimidine analogs. These studies provide mechanistic insight defining how autophagy inhibition can be leveraged to treat pancreatic cancer.

cancer biology↗

bioRxiv2024

Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models

Chronic pancreatitis (CP) affects [~]3 million people worldwide, yet altering the course of disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 36 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wildtype CFTR. Clinically available CFTR modulators stabilized mutant or wildtype CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides the first comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.

cell biology↗

bioRxiv2023

PCP components control anterior and posterior regeneration, with a Prickle homolog impacting muscle organization, in the acoel Hofstenia miamia

Whole-body regeneration requires wound response signals to control patterning programs to enable replacement of structures in their correct locations. While a number of molecular mechanisms underlying anterior-posterior regeneration have been identified, how small fragments of animals first re-establish polarity is less well understood, with non-canonical Wnt signaling recently emerging as a potential regulator. Here, we used the acoel worm Hofstenia miamia, a new research organism capable of robust whole-body regeneration, to assess functions of the components of the Planar Cell Polarity (PCP) pathway in establishing regeneration polarity. We identified homologs of Prickle (pk-1) and Diego (dgo-1) to be required for head and tail regeneration, respectively. RNA-sequencing analysis and experimental corroboration revealed that pk-1 RNAi resulted in diminished expression of early wound response genes as well as of wound-induced expression of the anterior-specific marker fz-7, specifically in tail fragments. In contrast, dgo-1 RNAi impacted wound-induced expression of the posterior-specific marker tf7l2, specifically in head fragments. Furthermore, pk-1 and dgo-1 are enriched in longitudinal muscle, with muscle fibers showing disorganized morphology at anterior-facing wound sites of tail fragments under pk-1 RNAi. These findings suggest that pk-1 and dgo-1 are needed for wound-induced expression of anterior- and posterior-specific genes, and raise the possibility that this action is mediated via the control of muscle fiber orientation. Our work expands the study of PCP genes by revealing their functions in the process of whole-body regeneration in acoels, the sister-group to all other animals with bilateral symmetry, and will enable future studies of PCP components in controlling cellular and tissue-wide regeneration polarity.

developmental biology↗