An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

Dhimolea, Eugen; Simoes, Ricardo de Matos; Kansara, Dhvanir; Al’Khafaji, Aziz; Bouyssou, Juliette; Weng, Xiang; Sharma, Shruti; Raja, Joseline; Awate, Pallavi; Shirasaki, Ryosuke; Tang, Huiping; Glassner, Brian J.; Liu, Zhiyi; Gao, Dong; Bryan, Jordan; Bender, Samantha; Roth, Jennifer A.; Scheffer, Michal; Jeselsohn, Rinath; Gray, Nathanael S.; Georgakoudi, Irene; Vázquez, Francisca; Tsherniak, Aviad; Chen, Yu; Welm, Alana L.; Duy, Cihangir; Melnick, Ari; Bartholdy, Boris; Brown, Myles; Culhane, Aedín; Mitsiades, Constantine S.

doi:10.1016/j.ccell.2020.12.002

Cited by 181 publications

(170 citation statements)

References 66 publications

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“…Research. Our findings are consistent with a report that investigated drug-resistance in solid tumors and revealed that the drug-persistent state shares a diapause-like dormancy signature (70). The diapause principle in theory represents a long-term dormancy state.…”

Section: Discussionsupporting

confidence: 93%

Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence

et al. 2021

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Acute myeloid leukemia (AML) patients frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA-seq suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential. SIGNIFICANCE Despite entering complete remission after chemotherapy, relapse occurs in many AML patients. Thus, there is an urgent need to understand the relapse mechanism in AML and the development of targeted treatments to improve outcome. Here, we identified a senescence-like resilience phenotype through which AML cells can survive and repopulate leukemia. Research.

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Section: Discussionsupporting

confidence: 93%

Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence

et al. 2021

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“…Different consensual models have been proposed to explain the survival of residual or dormant cancer cells, most of which are based on pre-exiting rare sub-clones that carry mutations conferring resistance to therapies. However, numerous recent studies are elevating the importance of non-mutational mechanisms and propose that mutation-induced resistance could not be the main mechanism leading to dormancy 24,25 . Interestingly, observations suggest that dormancy can be an adaptive strategy for cancers during times of stress 26 and in cases where undetectable residual cancer cells make the patient asymptomatic.…”

Section: How Do Dormant Cells Resist Anti-cancer Therapies?mentioning

confidence: 99%

“…that dormant cells are not a pre-exiting population in tumours, but that cancer cells have an equipotent ability to enter the dormant state, similar to the embryonic diapause 24,25 . The origin of dormant cancer cells in tumour relapse remain elusive; whether these dormant cells pre-exist in the tumour and chemotherapy promotes their selection, or cancer therapies induce their transition to a dormant state in a subpopulation of cancer cells still needs to be confirmed.…”

Section: How Do Dormant Cells Resist Anti-cancer Therapies?mentioning

confidence: 99%

“…Recent studies have suggested that quiescent cells could have an embryonic diapause-like state in breast and colorectal cancers. This diapause-like state is defined by decreased mTOR activity, leading to increased autophagy, suggesting that chemotherapy combined with autophagy inhibitors could be efficient to kill these quiescent cancer cells 24,25 . However, a deeper analysis of their transcriptomic signature demonstrates that this quiescent cancer cells might be distinct from the diapause state described for embryos, but rather resemble the paused embryonic stem cells 24 .…”

Section: Quiescent Cells Vs Senescent Cellsmentioning

confidence: 99%

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When dormancy fuels tumour relapse

Santos-de-Frutos

Djouder

2021

Commun Biol

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Tumour recurrence is a serious impediment to cancer treatment, but the mechanisms involved are poorly understood. The most frequently used anti-tumour therapies—chemotherapy and radiotherapy—target highly proliferative cancer cells. However non- or slow-proliferative dormant cancer cells can persist after treatment, eventually causing tumour relapse. Whereas the reversible growth arrest mechanism allows quiescent cells to re-enter the cell cycle, senescent cells are largely thought to be irreversibly arrested, and may instead contribute to tumour growth and relapse through paracrine signalling mechanisms. Thus, due to the differences in their growth arrest mechanism, metabolic features, plasticity and adaptation to their respective tumour microenvironment, dormant-senescent and -quiescent cancer cells could have different but complementary roles in fuelling tumour growth. In this review article, we discuss the implication of dormant cancer cells in tumour relapse and the need to understand how quiescent and senescent cells, respectively, may play a part in this process.

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“…However, in contrast to MSPC PCOs, cluster 3 LNCaP cells were depleted of E2F_TARGETS, G2M_CHECKPOINT and DNA_REPAIR signatures, presumably because enzalutamide induces cell cycle arrest and inhibits the expression of DNA repair genes (Li et al, 2017) (Figure S4D). Furthermore, cluster 3 cells were enriched of genes overexpressed by embryonic diapause-like dormant pluripotent stem cells, associated with MYC inactivation and tumor cell persistence against treatment (Boroviak et al, 2015;Dhimolea et al, 2021;Scognamiglio et al, 2016). To examine the clinical relevance of the transition from cluster 5 to cluster 3, we re-examined the transcriptional pro les of the nonresponders in the MDACC neoadjuvant enzalutamide + abiraterone dataset (Efstathiou et al, 2016).…”

Section: Single Cell Analysis Delineates the Trajectory From Arpc To Mspcmentioning

confidence: 99%

Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer

Han

Wang

Curto

et al. 2021

Preprint

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Unsupervised clustering and deconvolution analysis identifies a novel subtype of M-CRPC endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of patient datasets and mechanistic studies indicate that MSPC arises as a consequence of therapy-induced lineage plasticity. AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP signaling, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. The drug-tolerant prostate cancer cells generated through reprogramming are rescued by neuregulin and generate metastases in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. These results identify a novel subtype of M-CRPC, trace its origin to therapy-induced lineage plasticity, and reveal its dependency on HER2/3 signaling.

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An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

Cited by 181 publications

References 66 publications

Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence

Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence

When dormancy fuels tumour relapse

Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer

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