Biology subjects

Hemmes, A.

Publications and source records attributed to Hemmes, A..

5 recordsLinked to original sources

bioRxiv2024

Fibroblast activation protein defines aggressive EMT-associated cancer cell state and prognosis in localized ccRCC

Clear cell renal cell carcinoma (ccRCC) is among the most immune-infiltrated cancers, where high inflammation correlates with poor clinical outcomes. While epithelial-to-mesenchymal transition (EMT), immunosuppression, and cancer-associated fibroblasts (CAFs) have been linked with poor prognosis in metastatic ccRCC, their relevance and interplay in localized disease remain uncertain. To address this gap, we performed single-cell spatial profiling of highly inflamed localized tumors to characterize interactions between EMT-associated cancer cells and immune subsets, aiming to identify tumor microenvironment cell subsets and states responsible for the poor prognosis in highly inflamed ccRCC. Multiplexed immunofluorescence imaging with a 33-marker panel was applied to 1,728 tissue cores collected from tumor centers, invasive borders, and adjacent benign tissue from 435 localized ccRCC patients. Independent discovery (n=196) and validation (n=239) cohorts were used to confirm the significance of identified prognostic markers. Hierarchical clustering revealed TME subsets enriched for CD45 immune cells, CD31 endothelial cells, or fibroblasts. High CD45 cell density significantly correlated with poor recurrence-free survival across tumor regions, including tumor center, invasive border, and adjacent benign tissue. Within tumors exhibiting high CD45 infiltration, EMT-associated cancer cells strongly expressed fibroblast activation protein (FAP) at invasive borders, independently predicting worse prognosis and increased risk of liver metastasis. Furthermore, CD45high tumors with elevated FAP expression featured immunosuppressive FAP CAFs, M2-like macrophages, exhausted T cells, and regulatory T cells. Tumor-cell-specific FAP expression was validated as an independent prognostic biomarker in both early-stage localized ccRCC (pT1-2) and patients subsequently developing metastases who received sunitinib, highlighting its potential for improved patient stratification. SignificanceFAP expression identifies an aggressive, immunosuppressive EMT-associated subtype of localized ccRCC, uncovering critical interactions between cancer cells and the TME and revealing novel biological insights and therapeutic vulnerabilities driving early-stage ccRCC progression. Graphical AbstractO_ST_ABSTumor-cell FAP Expression Defines an Aggressive, Immunosuppressive EMT Subtype in Highly Inflamed Localized ccRCCC_ST_ABS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/620479v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@d25831org.highwire.dtl.DTLVardef@19c0de7org.highwire.dtl.DTLVardef@54bd9eorg.highwire.dtl.DTLVardef@16d0387_HPS_FORMAT_FIGEXP M_FIG C_FIG Localized ccRCC tumors were stratified by CD45 immune infiltration, revealing that CD45high tumors were associated with significantly poorer recurrence-free survival (5-year RFS rate: 39%). Among these, tumor cell-specific expression of fibroblast activation protein (FAP) identified a particularly aggressive subtype marked by epithelial-to-mesenchymal transition (EMT), reduced endothelial content, and an immunosuppressive tumor microenvironment enriched with M2-like macrophages, regulatory T cells, exhausted T cells, and FAP cancer-associated fibroblasts (CAFs). FAP tumors had an even lower 5-year RFS rate of 26%, compared to 50% in FAP- CD45high tumors. Tumor-cell FAP thus provides an additional layer of risk stratification within the CD45high subgroup and reflects a biologically distinct, immune-evasive tumor state. These findings highlight FAP as both a potential therapeutic target and imaging biomarker in localized ccRCC.

cancer biology↗

bioRxiv2022

Development of an adenosquamous carcinoma histopathology-selective lung cancer graft model

Preclinical tumor models with native tissue microenvironments provide essential tools to understand how heterogeneous tumor phenotypes relate to drug response. Here, we present syngeneic graft models of aggressive, metastasis-prone histopathology-specific NSCLC tumor types driven by KRAS mutation and loss of LKB1 (KL): adenosquamous carcinoma (ASC) and adenocarcinoma (AC). We show that subcutaneous injection of primary KL-ASC cells results in squamous cell carcinoma (SCC) tumors with high levels of stromal infiltrates, lacking the source heterogeneous histotype. Despite forming subcutaneous tumors, intravenously injected KL-AC cells were unable to form lung tumors. In contrast, intravenous injection of KL-ASC cells leads to their lung re-colonization and lesions recapitulating the mixed AC and SCC histopathology, tumor immune suppressive microenvironment and oncogenic signaling profile of source tumors, demonstrating histopathology-selective phenotypic dominance over genetic drivers. Pan-ERBB inhibition increased survival, while selective ERBB1/EGFR inhibition did not, suggesting a role of ERBB network crosstalk in resistance to ERBB1/EGFR. This immunocompetent NSCLC lung colonization model hence phenocopies key properties of the metastasis-prone ASC histopathology, and serves as a preclinical model to dissect therapy responses and metastasis-associated processes.

cancer biology↗

bioRxiv2021

PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer

For non-small cell lung cancer (NSCLC) patients with ALK-rearranged tumors, treatment with ALK inhibitors can improve outcomes. However, clinical resistance typically develops over time, and in the majority of cases resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen, and deployed functional drug screens to identify modulators of resistance to ALK inhibitors. This identified a role for PI3K{beta} and EGFR in regulating resistance to ALK inhibition. Furthermore, inhibition of ALK elicited activation of EGFR, and inhibition of PI3K{beta} rescued EGFR-mediated ALK inhibitor resistance. In ALK-rearranged primary cultures, cell lines and in vivo xenograft models, combined inhibition of ALK and PI3K{beta} prevented compensatory MAPK and PI3K-AKT pathway reactivation and selectively targeted the cancer cells. The combinatorial effect was seen even in the background of TP53 mutations and in epithelial-mesenchymal transformed cells. In conclusion, combinatorial ALK and PI3K{beta} inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.

cancer biology↗

bioRxiv2020

The role of SOX9 in non-small cell lung cancer progression is histopathology-selective.

The transcription factor SOX9 is a key regulator of multiple developmental processes, and is frequently re-expressed in non-small cell lung cancer (NSCLC). Its precise role in the progression of NSCLC histopathologies has however remained elusive. We show that SOX9 expression relates to poor outcome and invasive histopathology in human adenocarcinomas, and is absent in murine early minimally invasive and human in situ adenocarcinoma. Interestingly, despite wide SOX9 expression across advanced NSCLC histotypes, its genetic deletion in the murine KrasG12D;Lkb1-/- model selectively disrupted only the growth of papillary NSCLC, without affecting the initiation of precursor lesions or growth of mucinous or squamous tissue. Spatial tissue phenotyping indicated a requirement of SOX9 expression for the progression of surfactant protein C-expressing progenitor cells, which gave rise to papillary tumours. Intriguingly, while SOX9 expression was dispensable for squamous tissue formation, its loss in fact led to enhanced squamous tumour metastasis, which was associated with altered collagen IV deposition in the basement membrane. Our work therefore demonstrates histopathology-selective roles for SOX9 in NSCLC progression, namely a requirement for papillary adenocarcinoma progression, but opposing metastasis-suppressing function in squamous histotype tissue. This attests to a pleiotropic SOX9 function, linked to the cell of origin and microenvironmental tissue contexts.

cancer biology↗

bioRxiv2020

Functional diagnostics using fresh uncultured lung tumor cells to guide personalized treatments

Functional profiling of a cancer patients tumor cells holds potential to tailor personalized cancer treatment. Here we report the utility of Fresh Uncultured Tumor-derived EpCAM+ epithelial Cells (FUTC) for ex vivo drug response interrogation. Analysis of murine Kras mutant FUTCs demonstrated pharmacological and adaptive signaling profiles comparable to subtype-matched cultured cells. Applying FUTC profiling on non-small cell lung cancer patient samples, we generated robust drug response data in 18 of 19 cases, where the cells exhibited targeted drug sensitivities corresponding to their oncogenic drivers. In one of these cases, an EGFR mutant lung adenocarcinoma patient refractory to osimertinib, FUTC profiling was used to guide compassionate treatment. FUTC profiling identified selective sensitivity to disulfiram and the combination of carboplatin plus etoposide and the patient received substantial clinical benefit from the treatment with these agents. We conclude that FUTC profiling provides a robust, rapid, and actionable assessment of personalized cancer treatment options.

cancer biology↗