Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer

Javellana, Melissa; Eckert, Mark A.; Heide, Janna; Zawieracz, Katarzyna; Weigert, Melanie; Ashley, Sarah; Stock, Elizabeth; Chapel, David; Huang, Lei; Yamada, S. Diane; Ahmed, Ahmed A.; Lastra, Ricardo R.; Chen, Mengjie; Lengyel, Ernst

doi:10.1158/0008-5472.can-21-1467

Cited by 22 publications

(22 citation statements)

References 20 publications

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“…C Expression of MGP in 19 patients before and after neoadjuvant chemotherapy (NACT). The data are obtained from the RNA-sequencing dataset published by Javellana et al [ 45 ], and are expressed as reads per kilobase million (RPKM). *** p < 0.001.…”

Section: Resultsmentioning

confidence: 99%

Matrix Gla Protein drives stemness and tumor initiation in ovarian cancer

et al. 2023

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Ovarian cancer (OC) displays the highest mortality among gynecological tumors, mainly due to early peritoneal dissemination, the high frequency of tumor relapse following primary debulking, and the development of chemoresistance. All these events are thought to be initiated and sustained by a subpopulation of neoplastic cells, termed ovarian cancer stem cells (OCSC), that are endowed with self-renewing and tumor-initiating properties. This implies that interfering with OCSC function should offer novel therapeutic perspectives to defeat OC progression. To this aim, a better understanding of the molecular and functional makeup of OCSC in clinically relevant model systems is essential. We have profiled the transcriptome of OCSC vs. their bulk cell counterpart from a panel of patient-derived OC cell cultures. This revealed that Matrix Gla Protein (MGP), classically known as a calcification-preventing factor in cartilage and blood vessels, is markedly enriched in OCSC. Functional assays showed that MGP confers several stemness-associated traits to OC cells, including a transcriptional reprogramming. Patient-derived organotypic cultures pointed to the peritoneal microenvironment as a major inducer of MGP expression in OC cells. Furthermore, MGP was found to be necessary and sufficient for tumor initiation in OC mouse models, by shortening tumor latency and increasing dramatically the frequency of tumor-initiating cells. Mechanistically, MGP-driven OC stemness was mediated by the stimulation of Hedgehog signaling, in particular through the induction of the Hedgehog effector GLI1, thus highlighting a novel MGP/Hedgehog pathway axis in OCSC. Finally, MGP expression was found to correlate with poor prognosis in OC patients, and was increased in tumor tissue after chemotherapy, supporting the clinical relevance of our findings. Thus, MGP is a novel driver in OCSC pathophysiology, with a major role in stemness and in tumor initiation.

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Section: Resultsmentioning

confidence: 99%

Matrix Gla Protein drives stemness and tumor initiation in ovarian cancer

et al. 2023

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“…(C) Expression of MGP in 19 patients before and after neoadjuvant chemotherapy (NACT). The data are obtained from the RNA-sequencing dataset published by Javellana et al [37], and are expressed as reads per kilobase million (RPKM). *** p<0.001.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, given that chemotherapy has been proposed to promote stem-like traits in OC cells [34][35][36], we investigated the expression levels of MGP in paired samples of OC collected from 19 patients before and after chemotherapy [37]. MGP was found to be consistently upregulated in post-treatment samples (Fig.…”

Section: The Clinical Relevance Of Mgp In Ocmentioning

confidence: 99%

Matrix Gla Protein acts as a driver of stemness and tumor initiation in ovarian cancer

Nieddu

Melocchi

Battistini

et al. 2022

Preprint

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Ovarian cancer (OC) displays the highest mortality among gynecological tumors, mainly due to early peritoneal dissemination, the high frequency of tumor relapse following primary debulking and the development of chemoresistance. All these events are thought to be initiated and sustained by a subpopulation of neoplastic cells, termed ovarian cancer stem cells (OCSC), that are endowed with self-renewing and tumor-initiating properties. This implies that interfering with OCSC function should offer novel therapeutic perspectives to defeat OC progression. To this aim, a better understanding of the molecular and functional makeup of OCSC in clinically relevant model systems is essential. We have profiled the transcriptome of OCSC vs. their bulk cell counterpart from a panel of patient-derived OC cell cultures. This revealed that Matrix Gla Protein (MGP), classically known as a calcification-preventing factor in cartilage and blood vessels, is markedly enriched in OCSC. Functional assays showed that MGP confers several stemness-associated traits to OC cells, including a transcriptional reprogramming. Patient-derived organotypic cultures pointed to the peritoneal microenvironment as a major inducer of MGP expression in OC cells. Furthermore, MGP was found to be necessary and sufficient for tumor initiation in OC mouse models, by shortening tumor latency and increasing dramatically the frequency of tumor-initiating cells. Mechanistically, MGP-driven OC stemness was mediated by the stimulation of Hedgehog signaling, in particular through the induction of the Hedgehog effector GLI1, thus highlighting a novel MGP/Hedgehog pathway axis in OCSC. Finally, MGP expression was found to correlate with poor prognosis in OC patients, and was increased in tumor tissue after chemotherapy, supporting the clinical relevance of our findings. Thus, MGP is a novel driver in OCSC pathophysiology, with a major role in stemness and in tumor initiation.

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“…Previous studies of HGSC evolution have examined multiple samples taken at primary surgery, revealing significant intra-patient heterogeneity with evidence of diverse metastatic processes and patterns of clonal expansion [36][37][38] . Analyses before and after neoadjuvant chemotherapy have also failed to observe recurrent chemotherapy-induced mutations, but did suggest copy number alterations, including SIK2 amplification 39 . We did not identify any cases with SIK2 amplification or any difference in SIK2 absolute copy number (SIK2 median copies; diagnosis = 2.04 versus relapse = 1.99, p=0.41, Mann-Whitney U).…”

Section: Discussionmentioning

confidence: 99%

The genomic landscape of recurrent ovarian high grade serous carcinoma: the BriTROC-1 study

Smith

Bradley

Gavarró

et al. 2022

Preprint

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The drivers of recurrence and resistance in ovarian high grade serous carcinoma (HGSC) remain unclear. We established BriTROC-1 to investigate the acquisition of resistance by collecting tumour biopsies from women with recurrent ovarian HGSC that had relapsed following at least one line of platinum-based chemotherapy. Patients underwent biopsy or secondary debulking surgery, with tumour samples fixed in methanol-based fixative. Normal and tumour DNA samples underwent tagged-amplicon panel sequencing. Tumour DNA underwent shallow whole genome sequencing (sWGS). Tissue microarrays (TMA), created from diagnosis samples, were stained for CD3, CD8, CD20 and FoxP3. 276 patients were recruited (209 platinum-sensitive, 67 platinum-resistant). Panel sequencing showed close concordance between diagnosis and relapse, with only 4 discordant cases, and no revertant mutations inBRCA1orBRCA2were identified in relapse samples. CN signatures were strongly correlated with immune cell infiltration. There was very strong concordance in copy number (CN) between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic CN alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Small increases in CN signature 3 and 7 exposure were observed between diagnosis and relapse across the whole cohort but were not present in matched sample pairs. Diagnosis samples from patients with primary platinum resistance had increased rates ofCCNE1andKRASamplification and CN signature 6 exposure. The HGSC genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers. We have identified new genomic events at diagnosis, includingKRASamplification and CN signature 6 exposure, that are associated with primary platinum resistance.

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Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer

Cited by 22 publications

References 20 publications

Matrix Gla Protein drives stemness and tumor initiation in ovarian cancer

Matrix Gla Protein drives stemness and tumor initiation in ovarian cancer

Matrix Gla Protein acts as a driver of stemness and tumor initiation in ovarian cancer

The genomic landscape of recurrent ovarian high grade serous carcinoma: the BriTROC-1 study

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