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Therapy-induced senescence of cancer-associated fibroblasts determines survival in rectal cancer

ABSTRACT: Standard therapy of rectal cancer comprises a combination of local radio- and systemic chemotherapy prior to surgery. Despite comparable tumor morphology and stage the outcome of such neoadjuvant therapy is heterogeneous and the underlying factors that define therapy response are unknown. Here we demonstrate that cancer-associated fibroblasts (CAFs) rather than tumor cells themselves have major impact on therapy response and survival in a novel pre-clinical in vivo model of rectal cancer as well as in patients. We show that irradiation of tumors increases DNA damage further in inflammatory CAFs causing them to undergo a p53-dependent senescence program, which is associated with the secretion of various extracellular matrix components that strongly promote therapy resistance and progression. Administration of venetoclax (senolytics) renders therapy-resistant mice sensitive to irradiation. Collectively, we demonstrate how inflammatory polarization of CAFs affects cancer therapy and identify IL-1 signaling as an attractive target to repolarize CAFs in neoadjuvant therapy of rectal cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156281 | GEO | 2023/08/12

REPOSITORIES: GEO

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Project description:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients. 48 samples included in the study were analyzed on whole genome BAC arrays with the aim to characterize genomic alterations and correlate them with the tumor response to therapy. The case series was composed by 15%,81% and 4% of uT2, uT3 and uT4 tumors, respectively. At the diagnosis 56% of patients had uN0 tumors and 44% uN+. 30%,13%, 23% and 34% of patients reached/mantained respectively ypT0, ypT1, ypT2 and ypT3. With regard to response to NCRT, according to TRG criteria proposed by Dworak, two group were defined: non responders (TRG0-2= 56%) and responders (TRG3-4=44%). Clinical and pathological parameters: uT: pre-therapy stage determined by ultrasounds techniques uN: pre-therapy lymph node status determined by ultrasounds techniques ypT: pathologic stage after a neoadjuvant treatment ypN: pathologic lymph node status after a neoadjuvant treatment

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Therapy-induced senescence of cancer-associated fibroblasts determines survival in rectal cancer

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