Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer

Ruscetti, Marcus; Mezzadra, Riccardo; Russell, James M.; Leibold, Josef; Romesser, Paul B.; Simon, Janelle; Kulick, Amanda; Ho, Yu-Jui; Fennell, Myles; Li, Jinyang; Norgard, Robert J.; Wilkinson, J. Eric; Alonso-Curbelo, Direna; Sridharan, Ramya; Heller, Daniel A.; Stanchina, Elisa de; Stanger, Ben Z.; Sherr, Charles J.; Lowe, Scott W.

doi:10.1016/j.cell.2021.07.028

Cited by 52 publications

(57 citation statements)

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“…Most recently, studies have indicated that palbociclib may also prevent cell cycle entry by indirectly inhibiting CDK2, via increasing p21 abundance, and as such arrests cell cycle entry even when Cdk4s kinase activity is already impaired [152][153][154] . In addition, current studies show promising results by combining Cdk4/6 inhibitors with mitogen-activated protein kinase pathway inhibitors in KRAS-driven lung and pancreatic cancers mouse models 155,156 . Senescence induced by the combination of these cytostatic drugs is much more pronounced than single drug treatment alone.…”

Section: [H2] Forcing Cancer Cells To Permanently Exit the Cell Cyclementioning

confidence: 89%

Cell cycle control in cancer

Matthews

Bertoli

Bruin

2021

Nat Rev Mol Cell Biol

590

415

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Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated via multiple evolutionary-conserved cell cycle control mechanisms to ensure the production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints can delay cell cycle progression or, in response to irreparable DNA damage, induce cell cycle exit or cell death. Cancer-associated mutations that perturb cell cycle control allow continuous cell division chiefly by compromising the ability of cells to exit the cell cycle. Continuous rounds of division however, creates increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain viability . New detailed insights into cell cycle control mechanisms and their role in cancer reveal how these dependencies can be best exploited in cancer treatment.[H2] Cell cycle phases. The mitotic cell cycle is divided into two distinct stages, interphase and M phase (Figure 1). This allows for the temporal separation of the duplication of cellular content during interphase and its separation into two genetically identical daughter cells in mitosis. The complex network of regulatory elements that form the cell cycle has one goal: the timely and accurate duplication and segregation of the genomic DNA. DNA replication takes place in interphase during S phase (Synthesis phase),defined as the time in interphase during which DNA replication has been initiated but not completed. The periods of interphase that separate S phase from M-phase have historically been named Gap phases, or G1 before S phase and G2 after S phase, based on the evident observation that these are gaps inbetween the two main events, duplication and segragation of the DNA. However, these phases are key periods for cell cycle regulation and include the crucial decision to enter the cell cycle during G1, and to initiate the process that leads to chromosome segregation during G2.[H2] Cell cycle entry and progression. Before S-phase, in the pre-replicative G1 phase, there is a decision window during which cells can commit to initiate DNA replication and enter the cell cycle or stay in G1 phase (Figure 1). During G1 cells can also exit the cell cycle into a non-proliferative state known as quiescence, or G0. The vast majority of cells in an adult body are in a non-proliferative state and would need to transit into G1 before being able to initiate DNA replication and enter the cell cycle. Upon completion of DNA replication, there is another decision window during the post-replicative G2 phase. During this window, cells can commit to enter M phase by initiating chromatin condensation and the central alignment of chromosomes. M phase serves the dual function of both accurately separating the duplicated DNA (mitosis) and dividing the entire cellular content into two new daughter cells (cytokinesis). During M phase, cells commit to t...

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Section: [H2] Forcing Cancer Cells To Permanently Exit the Cell Cyclementioning

confidence: 89%

Cell cycle control in cancer

Matthews

Bertoli

Bruin

2021

Nat Rev Mol Cell Biol

590

415

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“…Finally, CDK4/6 inhibition can re‐sensitize tumours to immune checkpoint blockade (Xue et al , 2007; Krizhanovsky et al , 2008; Kang et al , 2011; Acosta et al , 2013; Goel et al , 2017; Chaikovsky & Sage, 2018; Deng et al , 2018; Jerby‐Arnon et al , 2018; Ruscetti et al , 2018, 2020). The ability of CDK4/6 inhibition to inhibit DNA replication could help to promote immune engagement in a number of different ways.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it can induce senescence, thereby creating non-proliferative tumour cells that continually secrete factors to engage the immune system (Xue et al, 2007;Krizhanovsky et al, 2008;Kang et al, 2011;Acosta et al, 2013). CDK4/6 inhibitor-induced senescence helps to sensitize tumours to immune checkpoint blockade (Jerby-Arnon et al, 2018;Ruscetti et al, 2018Ruscetti et al, , 2020, therefore it will be important to test whether replication stress leads to senescence in these settings. There are currently 14 clinical trials ongoing in 8 tumour types to assess whether CDK4/6 inhibition can improve response to anti-cancer immunotherapy (Wagner & Gil, 2020), therefore it will also be important to assess whether p53 status correlates with response in these situations.…”

Section: Discussionmentioning

confidence: 99%

“…There are many different potential explanations, including that CDK4/6 inhibition can induce senescence, apoptosis, metabolic reprogramming and/or anti-tumour immunity (for reviews see (Goel et al, 2018;Klein et al, 2018)), but whether a common event underlies these different outcomes is unclear. There is good evidence that some of the long-term outcomes are linked, in particular, senescent cells can secrete a variety of factors that engage the immune system (Xue et al, 2007;Krizhanovsky et al, 2008;Kang et al, 2011;Acosta et al, 2013), and this senescence phenotype contributes to the ability of CDK4/6 inhibition to sensitize tumours to immune checkpoint blockade (Jerby-Arnon et al, 2018;Ruscetti et al, 2018Ruscetti et al, , 2020. It is therefore critical to determine how and why G1-arrested cells eventually become senescent because this may help to inform ongoing clinical trials assessing CDK4/6 inhibition alongside immunotherapy (currently 14 trials in eight different cancer types (Wagner & Gil, 2020)).…”

Section: Introductionmentioning

confidence: 99%

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CDK4/6 inhibitors induce replication stress to cause long‐term cell cycle withdrawal

et al. 2022

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CDK4/6 inhibitors arrest the cell cycle in G1‐phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long‐lasting effects on tumour growth. Here, we demonstrate that a prolonged G1 arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. Upon release from that arrest, many cells fail to complete DNA replication and exit the cell cycle in a p53‐dependent manner. If cells fail to withdraw from the cell cycle following DNA replication problems, they enter mitosis and missegregate chromosomes causing excessive DNA damage, which further limits their proliferative potential. These effects are observed in a range of tumour types, including breast cancer, implying that genotoxic stress is a common outcome of CDK4/6 inhibition. This unanticipated ability of CDK4/6 inhibitors to induce DNA damage now provides a rationale to better predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress.

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“…Similarly, Wang et al have shown that sunitinib-induced senescence stimulates endothelial cells to secrete pro-inflammatory cytokines, thus promoting cancer metastasis and invasion [ 175 ]. In contrast with those studies, Ruscetti et al have demonstrated that the induction of senescence in PDAC cells, through the use of a combination of palbociclib and trametinib, induced vascular remodeling within the tumor, increasing its sensitivity to cytotoxic drugs and promoting T-cell infiltration [ 176 ]. This opposing evidence highlights the necessity of improving the knowledge on the effects of senescence in endothelial cells composing the TME.…”

Section: Senescence In Non-tumor Cellsmentioning

confidence: 99%

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Cortesi

Zanoni

Pirini

et al. 2021

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) has one of the most dismal prognoses of all cancers due to its late manifestation and resistance to current therapies. Accumulating evidence has suggested that the malignant behavior of this cancer is mainly influenced by the associated strongly immunosuppressive, desmoplastic microenvironment and by the relatively low mutational burden. PDAC develops and progresses through a multi-step process. Early in tumorigenesis, cancer cells must evade the effects of cellular senescence, which slows proliferation and promotes the immune-mediated elimination of pre-malignant cells. The role of senescence as a tumor suppressor has been well-established; however, recent evidence has revealed novel pro-tumorigenic paracrine functions of senescent cells towards their microenvironment. Understanding the interactions between tumors and their microenvironment is a growing research field, with evidence having been provided that non-tumoral cells composing the tumor microenvironment (TME) influence tumor proliferation, metabolism, cell death, and therapeutic resistance. Simultaneously, cancer cells shape a tumor-supportive and immunosuppressive environment, influencing both non-tumoral neighboring and distant cells. The overall intention of this review is to provide an overview of the interplay that occurs between senescent and non-senescent cell types and to describe how such interplay may have an impact on PDAC progression. Specifically, the effects and the molecular changes occurring in non-cancerous cells during senescence, and how these may contribute to a tumor-permissive microenvironment, will be discussed. Finally, senescence targeting strategies will be briefly introduced, highlighting their potential in the treatment of PDAC.

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Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer

Cited by 52 publications

References 0 publications

Cell cycle control in cancer

Cell cycle control in cancer

CDK4/6 inhibitors induce replication stress to cause long‐term cell cycle withdrawal

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

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