Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intra-patient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAFs) in all patients. Besides inflammatory CAFs (iCAFs), vascular CAFs (vCAFs) and matrix CAFs (mCAFs), we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8 and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease. Implications: The newly characterized differences between ascitic and solid cancer cells before and after chemotherapy could inform novel treatment strategies for metastatic HGSOC.

In silico analysis and validation the cancer- associated fibroblasts related gene CAMK4 promotes bladder cancer progression

“…ALDH1A1 is critically involved in self-renewal, differentiation, and self-protection in various cancers, including lung, liver, ovarian, pancreatic, and breast cancers[26-28]. ALDH1A1 has also been found to be an important gene associated with CAFs in ovarian and prostate cancers [29,30]. Dihydroceramide desaturase 1 (DEGS1) plays a role in ceramide biosynthesis at the nal step of the sphingolipid pathway [31].…”

Exploring the diversity of cancer-associated fibroblasts: insights into mechanisms of drug resistance

“…The second category of myCAFs, also termed as such in studies, is typified by expression of collagen-encoding genes ( COL1A1 , COL10A1 , COL11A1 , CTHRC1 , etc. ), matrix metalloproteinases ( MMP11 ), non-collagenous ECM genes ( POSTN , THBS2 , and VCAN , FN1 ), and signal transduction genes ( SULF1 , INHBA ) ( Kieffer et al, 2020 ; Lin et al, 2020 ; Wang et al, 2021 ; Bischoff et al, 2022 ; Loret et al, 2022 ; Liu et al, 2023 ; Werba et al, 2023 ). These fibroblasts, also referred to as matrix CAFs (mCAFs) ( Zhang et al, 2020 ; Cords et al, 2023 ; Ma et al, 2023 ), ECM-remodeling CAFs ( Che et al, 2021 ; Giguelay et al, 2022 ), desmoplastic CAFs (dCAFs) ( Galbo et al, 2021 ), TGF-β-activated CAFs (TGFB CAFs) ( Hornburg et al, 2021 ), classical CAFs (cCAFs) ( Chen et al, 2021 ), and others ( Olbrecht et al, 2021 ; Deng et al, 2022 ; Pan et al, 2023 ), are intricately associated with ECM organization and remodeling, collagen production, TGF-β response and pathways governing the epithelial to mesenchymal transition (EMT).…”

“…Among the diverse CAF subtypes, iCAFs stand out for their distinct immunomodulatory secretory profile ( Figure 1 ). iCAFs are characterized by their expression of various genes, including members of the chemokine ligand family ( CXCL12 and CXCL14 ), the insulin-like growth factor family ( IGF1 and IGFBP6 ), complement-regulatory genes ( C3 , C7, and CFD), and some other genes ( APOD , FBLN1 , PTGDS , DPT, and GSN ) ( Elyada et al, 2019 ; Zhang et al, 2020 ; Chen et al, 2020 ; Wang et al, 2021 ; Galbo et al, 2021 ; Pu et al, 2021 ; Li et al, 2022 ; Chen et al, 2022 ; Li et al, 2022 ; Hu et al, 2022 ; Loret et al, 2022 ; Obradovic et al, 2022 ; Yang et al, 2022 ; Liu et al, 2023 ; Cords et al, 2023 ; Ma et al, 2023 ; Pan et al, 2023 ; Werba et al, 2023 ).…”

“…In this review, we systematically interrogate the landscape of CAF heterogeneity by leveraging scRNA-seq data encompassing diverse malignancies. In total, we reviewed and systematized data from 36 scRNA-seq studies, encompassing 17 types of human malignant tumors ( Elyada et al, 2019 ; Zhang et al, 2020 ; Chen et al, 2020 ; Dominguez et al, 2020 ; Kieffer et al, 2020 ; Lin et al, 2020 ; Wang et al, 2021 ; Zhang et al, 2021 ; Che et al, 2021 ; Chen et al, 2021 ; Galbo et al, 2021 ; Hornburg et al, 2021 ; Olbrecht et al, 2021 ; Pu et al, 2021 ; Li et al, 2022 ; Bischoff et al, 2022 ; Li et al, 2022 ; Chen et al, 2022 ; Li et al, 2022 ; Deng et al, 2022 ; Giguelay et al, 2022 ; Hu et al, 2022 ; Loret et al, 2022 ; Luo et al, 2022 ; Obradovic et al, 2022 ; Yang et al, 2022 ; Zhao et al, 2022 ; Liu et al, 2023 ; Qin et al, 2023 ; Liu et al, 2023 ; Zhang et al, 2023 ; Cords et al, 2023 ; Ma et al, 2023 ; Pan et al, 2023 ; Wang et al, 2023 ; Werba et al, 2023 ). As a result, we identified and characterized three primary CAFs populations: myofibroblast-like CAFs, inflammatory CAFs, and antigen-presenting CAFs.…”

Molecular Regulation and Oncogenic Functions of TSPAN8

“…Interestingly, various subtypes of cancer-associated fibroblasts (CAFs)-an important stromal cell population in the tumor microenvironment that assists in EMT, the invasion of cancer cells and cancer metastasis-are characterized by high TSPAN8 expression in high-grade serous ovarian cancer (HGSOC). However, whether enhanced TSPAN8 expression in CAFs and other stromal cells has an effect on the regulation of EMT, the invasion of cancer cells and cancer metastasis remains largely unknown [124].…”