Calcium Regulation
& Cancer Signaling:
Plain Language Summary

Starving Cancer of Calcium: How Lowering ER Levels Shuts Down Tumor Signaling

February 25th, 2026

Signaling systems are crucial for establishing cell function and identity, for promoting or restricting cell division, and therefore have a major role in maintaining tissue health and homeostasis. Cells can translate an extracellular signal into an appropriate response triggering a molecular cascade, starting at the membrane with a receptor all the way into the nucleus, often leading to specific gene expression. Disruption or mis-activation of these signals can result in tumor initiation and growth, and is a known hallmark of cancer. This 2019 study in Cell Reports reveals that several cancer-related signaling pathways are uniquely sensitive to levels of Calcium (Ca2+) present in the Endoplasmic Reticulum (ER). Their respective receptors and even some downstream components navigate through or interact with the secretory pathway.

The ER is the cell’s primary Ca2+ store. 

Ca2+ ER concentration is critical for maintaining high ATP levels necessary for chaperone activity on secreted and transmembrane proteins travelling through the secretory pathway. ER Ca2+ levels are tightly controlled by ER pumps like SERCA, Ca2+ sensors, and Ca2+ channels sitting on other membranes, like the plasma membrane (PM) or the mitochondria, that communicate with the ER.

Using the fruit fly and its powerful genetic tools, the authors tested different mutation combinations for ER pumps, sensors and PM channels to modulate ER Ca2+ concentration. They observed its impact on well-described conserved signaling pathways in vivo and in cultured cells.

Three oncogenic pathways disrupted by different ER Ca2+ levels

Their first striking observation was made with mutations in SERCA, which decreased ER Ca2+ levels. In cells carrying the strongest mutations (resulting in a non-functional pump), Wingless/Wnt signaling was shut down because its main mediator, Armadillo/Beta-catenin was trapped at the ER by E-cadherin, a cell adhesion molecule whose progress in the secretory pathway was stalled. The Hippo and Notch pathways were also disrupted, with their respective receptors, Fat and Notch accumulating in the ER and unable to reach the plasma membrane. 

Initially, these findings were unsurprising. Membrane proteins must go through the ER to reach the plasma membrane; if they can’t pass quality check because it is deficient with lowered Ca2+ levels in the ER, they simply stay there. What the authors did that took this work to the next level was to induce and define three thresholds of Ca2+ ER concentrations that induce three different levels of ER stress, which differentially affected the oncogenic signaling pathways. As a result, Wnt signaling showed to be the most sensitive as it was disrupted by slight decreases in ER Ca2+ levels, whereas Notch and Hippo signaling were sensitive to stronger intermediate levels of ER stress. A final level, caused by a null mutation in SERCA, ultimately led to cell death.

Using the ER Calcium pump as a cancer therapeutic target

This work has important implications for the use of SERCA inhibitors, such as Thapsigargin (Tg)-based drugs, to treat certain cancers. Several clinical trials have used it at higher doses to induce cell death specifically in cancerous cells, yet lower levels could be used to specifically block Wnt-driven tumorigenesis. However, the level of inhibition needed to prevent Notch signaling is likely to promote tumor invasiveness by disrupting Hippo signaling, as both pathways are equally sensitive to ER Ca2+ levels. Restoring and maintaining cellular homeostasis is indeed a fine line to walk, especially if you decide to meddle with the cell’s largest organelle.

Read the full article: Suisse A, Treisman JE. Cell Reports 2019.

Annabelle SUISSE, PhD