STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment

Abstract

A fascinating but uncharacterized action of antimitotic chemotherapy is to collectively prime cancer cells to apoptotic mitochondrial outer membrane permeabilization (MOMP), while impacting only on cycling cell subsets. Here, we show that a proapoptotic secretory phenotype is induced by activation of cGAS/STING in cancer cells that are hit by antimitotic treatment, accumulate micronuclei and maintain mitochondrial integrity despite intrinsic apoptotic pressure. Organotypic cultures of primary human breast tumors and patientderived xenografts sensitive to paclitaxel exhibit gene expression signatures typical of type I IFN and TNFα exposure. These cytokines induced by cGAS/STING activation trigger NOXA expression in neighboring cells and render them acutely sensitive to BCL-xL inhibition. cGAS/STING-dependent apoptotic effects are required for paclitaxel response in vivo, and they are amplified by sequential, but not synchronous, administration of BH3 mimetics. Thus anti-mitotic agents propagate apoptotic priming across heterogeneously sensitive cancer cells through cytosolic DNA sensing pathway-dependent extracellular signals, exploitable by delayed MOMP targeting.

Trial watch: STING agonists in cancer therapy

“…Among others, these agents include (1) radiation therapy, at least when administered according to optimal dose and fractionation schedules that do not favor the upregulation of the dsDNA-degrading enzyme three prime repair exonuclease 1 (TREX1), 46,55,63,[179][180][181] (2) molecules that cause DNA damage, such as cisplatin 182,183 and topoisomerase inhibitors like etoposide, [183][184][185][186] or compromise the DNA damage response, including the clinically employed poly(ADP)-ribose polymerase 1 (PARP) inhibitor olaparib, [187][188][189][190] as well as experimental inhibitors of ATR serine/threonine kinase (ATR), 191 or cause mitotic disturbances, such as paclitaxel and other taxanes. 35,192 Taken together, these observations suggest that several commonly used anticancer agents trigger STING-dependent cytokine responses. Besides contributing to therapeutic efficacy (at least to some degree), such responses may be actionable therapeutically, and hence need to be taken under attention consideration when combinatorial regimens are conceived.…”

Targeting of BCL-2 Family Members during Anticancer Treatment: A Necessary Compromise between Individual Cell and Ecosystemic Responses?

“…As a consequence, (possibly chemo-induced) epithelio-mesenchymal transition (EMT) in relation to ER stress-induced PERK signaling activation might increase dependence on BCL-xL and render necessary the use of specific inhibitors thereof [33,48,49]. Mechanistically, increased NOXA expression, observed upon antimitotic treatment [46,50,51], EMT [33] or ER stress [52], is expected to modify dependence of cancer cells on BCL-2 family proteins, shifting the burden to support viability from MCL-1 (buffered by NOXA) to BCL-xL exclusively. Dynamic NOXA expression may thus help predict BCL-xL inhibitors efficiency.…”

“…Targeting BCL-xL/BCL-2 with the first available dual inhibitors ABT-737 and navitoclax, exhibit potent synergy with several chemotherapeutics in difficult-to-treat tumors such as triple negative breast cancers or non-small cell lung carcinoma. BH3 mimetics inhibiting BCL-xL greatly enhanced antimitotic efficacy in exploiting the BCL-xL dependence resulting from NOXA induction by antimitotics [50]. BH3 mimetics also synergized with other on-target therapies such as inhibitors of oncogenic kinases that often induce upregulation of pro-apoptotic BH3-only proteins BIM, PUMA, or BMF and shifts between BCL-2 prosurvival dependence in cancer cells.…”

“…We indeed recently reported that proliferating breast cancer cells produce a TNFα and type I-IFN containing secretome upon antimitotic treatment. This relies on the activation of cGAS/STING pathway by antimitotic-induced micronuclei and leads to the spreading of an apoptotic predisposed phenotype in neighboring non proliferating cancer cells [50] (Figure 4). In the same way, cells committed to die can continue to signal to living cells in the surrounding tissue by producing cytokines during necroptosis as well as tumor immune response [108], or metabolites during apoptosis through pannexin-1 as mentioned above [134].…”

“…Therefore, treatment of donor cells with BH3 mimetics prevents them from mounting a pro-apoptotic secretome and might prevent spreading of death signaling across population. As a consequence, sequential schedules in combination protocols based on delayed BH3 mimetics administration, were more efficient to limit tumor progression than the same synchronous combination, which may underestimate BH3 mimetic anticancer potential [50]. The inflammatory nature of the intercellular communications underscores that the dose and time schedule of drug administration need to be conceived on the basis of their effects not only on cancer cell populations but also on host response.…”